(2S,3S)-2-benzhydryl-N-[(5-tert-butyl-2-methoxy-phenyl)methyl]quinuclidin-3-amine

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

(2S,3S)-2-benzhydryl-N-[(5-tert-butyl-2-methoxy-phenyl)methyl]quinuclidin-3-amine

EC Number:

831-973-7

Cas Number:

147116-67-4

Molecular formula:

C32H40N2O

IUPAC Name:

(2S,3S)-2-benzhydryl-N-[(5-tert-butyl-2-methoxy-phenyl)methyl]quinuclidin-3-amine

Test material form:

solid: granular

Remarks:

Granular white powder

Details on test material:

Granular white powder

Specific details on test material used for the study:

Sponsor's identification CJ-11,972
Description white solid
Batch number 52855-16-4
Date received 11 April 2001
Storage conditions room temperature in the dark

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Three New Zealand White rabbits were supplied by David Percival Ltd. Moston, Sandbach_
Cheshire, UK. At the start of the study the animals weighed 2.90 to 3.22 kg and were twelve to
sixteen weeks old. After an acclimatisation period of at least five days each animal was given a
number unique within the study which was written with a black indelible marker-pen on the inner
surface of the ear and on the cage label.
The animals were individually housed in suspended metal cages. Free access to mains drinking
water and food (STANRAB SQC Rabbit Diet. Special Diets Services Ltd. Witham, Essex, UK)
was allowed throughout the study. The diet and drinking water were considered not to contain
any contaminant of a level that might have affected the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 17 to 23°C and 30 to 70%
respectively. Any occasional deviations from these targets were considered not to have affected
the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per
hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00
to 18:00) and twelve hours darkness_

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 mL (31 mg)

Duration of treatment / exposure:

Treated eyes were not irrigated

Observation period (in vivo):

Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours
following treatment. Additional observations were made in one treated eye on Days 7, 14 and 21 to assess the
reversibility of the ocular effects.

Number of animals or in vitro replicates:

Three

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not washed
- Time after start of exposure: Substance not removed

SCORING SYSTEM: Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. according to the numerical evaluation given in Appendix 2. (from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances. National Academy of Sciences, Washington DC p.48 to 49)

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the
light source from a standard ophthalmoscope.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Results 2

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible

Results 3

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.66

Max. score:

2

Reversibility:

fully reversible

Results 4

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.66

Max. score:

2

Reversibility:

fully reversible

Results 5

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Results 6

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Results 7

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Results 8

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Results 9

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Results 10

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Results 11

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible

Results 12

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible

Any other information on results incl. tables

Off white residual test material was noted in and around the treated eye of one animal one hour after treatment and at the 24, 48 and 72-hour observations.

Diffuse corneal opacity was noted in one treated eye at the 24-hour observation. Residual test material adhered to a small area of the cornea and an area of the lower conjunctival membrane was noted in this treated eye and caused opaque corneal opacity at the 48. 72-hour and 7-day observations with translucent corneal opacity at the 14-day observation. No ocular effects were noted in the area of the cornea unaffected by the residual test material at the 48-hour and subsequent observations. Iridial inflammation was noted in this treated eye at the 24, 48 and 72- hour observations. Minimal conjunctival irritation was noted in this treated eye one hour after treatment with moderate conjunctival irritation at the 24 and 48 -hour observations and minimal conjunctival irritation at the 72-hour observation. This treated eye appeared normal at the 21-day observation. After consideration of the effects in the first treated eye two additional animals were treated. No corneal or iridial effects were noted in these treated eyes during the study. Minimal conjunctival irritation was noted in these two treated eyes one hour after treatment and in one of these treated eyes at the 24-hour observation. No other ocular effects were noted in these treated eyes during the study,

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The test material produced a group mean score of 12.3 at the 48-hour observation and was
classified as a Mill) IRRITANT (CLASS 4 ON A I TO 8 SCALE) to the rabbit eye according to
a modified Kay and Calandra classification system.
The test material did not meet the criteria for classification as irritant according to Eli labelling
regulations Commission Directive 93/21/EEC.